The presence of wild type p53 in hematological cancers improves the efficacy of combinational therapy targeting metabolism

// Nerea Allende-Vega 1, * , Ewelina Krzywinska 1, * , Stefania Orecchioni 2 , Nuria Lopez-Royuela 1 , Francesca Reggiani 2 , Giovanna Talarico 2 , Jean-François Rossi 3 , Rodrigue Rossignol 4, 5 , Yosr Hicheri 3 , Guillaume Cartron 3 , Francesco Bertolini 2 , Martin Villalba 1, 6 1 INSERM U1183, Université de Montpellier 1, UFR Médecine, Montpellier, France 2 Laboratory of Hematology-Oncology, European Institute of Oncology, Milan, Italy 3 Département d'Hématologie Clinique, CHU Montpellier, Université Montpellier 1, Montpellier, France 4 Laboratoire Maladies Rares: Génétique et Métabolisme (MRGM), Université de Bordeaux, Bordeaux, France 5 Cellomet, Amélie Rabat-Léon, Bordeaux, France 6 Institute for Regenerative Medicine and Biotherapy (IRMB), CHU Montpellier, Montpellier, France * These authors have contributed equally to this work Correspondence to: Martin Villalba, e-mail: martin.villalba@inserm.fr Nerea Allende-Vega, e-mail: nerea.allende-vega@inserm.fr Keywords: metabolism, oxidative phosphorylation, dichloroacetate, mutant p53, AMPK Received: January 29, 2015      Accepted: July 20, 2015      Published: July 30, 2015 ABSTRACT Manipulation of metabolic pathways in hematological cancers has therapeutic potential. Here, we determined the molecular mechanism of action of the metabolic modulator dichloroacetate (DCA) in leukemic cells. We found that DCA induces the AMP-activated protein kinase (AMPK)/p53 pathway with increased efficacy in tumors expressing wild type (wt p53). Clinically relevant, low concentrations of doxorubicin synergize in vitro and in vivo with DCA to further enhance p53 activation and to block tumor progression. Leukemia cell lines and primary leukemic cells containing mutant p53 are resistant to the above-described combination approach. However, DCA synergized with the Hsp90 inhibitor 17-AAG to specifically eliminate these cells. Our studies strongly indicate that depending on the p53 status, different combination therapies would provide better treatment with decreased side effects in hematological cancers.